A major objective of chronotherapy for cardiovascular diseases is to deliver the drug in higher concentrations during the time of greatest need, typically during the early morning hours, and in lesser concentrations when the need is less, such as during the late evening and early sleep hours. This can be accomplished by administration of the release dosage form of the present invention, which relates to a controlled absorption of propranolol from dosage forms. In particular, the present invention relates to a unit dosage form of an assembly of one or more bead populations, each of which is designed to release one or more therapeutic agents as a rapid or sustained release pulse after a predetermined delay (xe2x80x9ctime-controlledxe2x80x9d drug delivery instead of xe2x80x9crate-controlledxe2x80x9d) with resulting plasma concentration(s) of propranolol varying in a circadian rhythm fashion following administration of a single dosage form at bedtime, thereby minimizing potential risks of a stroke and/or heart attack and enhancing patient compliance and therapeutic efficacy, while reducing cost of treatment.
Many therapeutic agents are most effective when made available at a constant rate at or near the absorption site. The absorption of therapeutic agents thus made available generally results in desired plasma concentrations leading to maximum efficacy and minimum toxic side effects. Much effort has been devoted to developing sophisticated drug delivery systems, such as osmotic devices, for oral application. However, there are instances where maintaining a constant blood level of a drug is not desirable. For example, a xe2x80x9cposition-controlledxe2x80x9d drug delivery system (e.g., treatment of colon disease or use of colon as an absorption site for peptide and protein based products) may prove to be more efficacious. A pulsatile delivery system is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. However, there are only a few such orally applicable pulsatile release systems due to the potential limitation of the size or materials used for dosage forms. Ishino et al. disclose a dry-coated tablet form in Chemical Pharm. Bull. Vol. 40 (11), 3036-041 (1992). U.S. Pat. No. 4,851,229 to Magruder et al., U.S. Pat. No. 5,011,692 to Fujioka et al., U.S. Pat. No. 5,017,381 to Maruyama et al., U.S. Pat. No. 5,229,135 to Philippon et al., and U.S. Pat. No. 5,840,329 to Bai disclose preparation of pulsatile release systems. Some other devices are disclosed in U.S. Pat. No. 4,871,549 to Ueda et al. and U.S. Pat. Nos. 5,260,068; 5,260,069; and 5,508,040 to Chen. U.S. Pat. Nos. 5,229,135 and 5,567,441 both to Chen disclose a pulsatile release system consisting of pellets coated with delayed release or water insoluble polymeric membranes incorporating hydrophobic water insoluble agents or enteric polymers to alter membrane permeability. U.S. Pat. No. 5,837,284 to Mehta et al. discloses a dosage form which provides an immediate release dose of methylphenidate upon oral administration, followed by one or more additional doses spread over several hours.
The incidence of many cardiovascular diseases varies predictably in time over 24 hours, i.e., in a circadian rhythm fashion (See, e.g., Y. A. Anwar and W. B. White, Chronotherapeutics for Cardiovascular Disease, Drugs 1998, 55, pp 631-643, which is incorporated herein by reference). For example, a rapid increase in both acute myocardial infarction and systolic blood pressure has been reported in the well controlled studies on actual patients. In such cases, administration of a different kind of unit dosage form which delivers the drug in higher concentrations during the time of greatest need, typically during the early morning hours, and in lesser concentrations when the need is less, such as during late evening and early sleep hours. Commonly assigned and co-pending U.S. application Ser. No. 09/778,645, filed Feb. 7, 2001, which is incorporated in its entirety, discloses a pulsatile release system which includes a combination of two or three pellet populations, each with a well defined release profile. In accordance with the present invention, a plasma profile is obtained which varies in a circadian rhythm fashion following administration of the novel dosage form.
Propranolol [1-(isopropyl amino)-3-(1-naphthyloxy)-2-propanol] is a beta-adrenergic blocking agent and as such is a competitive inhibitor of the effects of catecholamines at beta-adrenergic receptor sites. The principal effect of propranolol is to reduce cardiac activity by diminishing or preventing beta-adrenergic stimulation. By reducing the rate and force of contraction of the heart, and decreasing the rate of conduction of impulses through the conducting system, the response of the heart to stress and exercise is reduced. These properties are used in the treatment of angina in an effort to reduce the oxygen consumption and increase the exercise tolerance of the heart. Propranolol is also used in the treatment of cardiac arrhythmias to block adrenergic stimulation of cardiac pacemaker potentials. Propranolol is also beneficial in the long term treatment of hypertension. Other uses of propranolol are in the treatment of migraine and anxiety.
Propranolol is normally administered as propranolol hydrochloride tablets.
The present invention provides a timed, sustained release multi-particulate dosage form comprising a propranolol core having a first membrane of a sustained release polymer and a second membrane of a mixture of water insoluble polymer and an enteric polymer (2nd or outer coating), wherein the water insoluble polymer and the enteric polymer may be present at a weight ratio of from 10:1 to 1:2, and the total weight of the coatings is 10 to 60 weight % based on the total weight of the coated beads. In some cases depending on the type of drug release profile needed, an immediate release component may be included to provide a modified, timed, sustained release dosage form. When administered at bedtime, the dosage form comprising one or more bead populations delivers the drug in lesser concentrations during the time of least need, for example, during late evening and early sleep hours, and in higher concentrations during the time of greatest need, for example, during the early morning hours.